Blinded, Multicenter Evaluation of Drug-induced Changes in Contractility Using Human-induced Pluripotent Stem Cell-derived Cardiomyocytes.

Animal models are 78% accurate in determining whether drugs will alter contractility of the human heart. To evaluate the suitability of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for predictive safety pharmacology, we quantified changes in contractility, voltage, and/or Ca2+ handling in 2D monolayers or 3D engineered heart tissues (EHTs). Protocols were unified via a drug training set, allowing subsequent blinded multicenter evaluation of drugs with known positive, negative, or neutral inotropic effects. Accuracy ranged from 44% to 85% across the platform-cell configurations, indicating the need to refine test conditions. This was achieved by adopting approaches to reduce signal-to-noise ratio, reduce spontaneous beat rate to ≤ 1 Hz or enable chronic testing, improving accuracy to 85% for monolayers and 93% for EHTs. Contraction amplitude was a good predictor of negative inotropes across all the platform-cell configurations and of positive inotropes in the 3D EHTs. Although contraction- and relaxation-time provided confirmatory readouts forpositive inotropes in 3D EHTs, these parameters typically served as the primary source of predictivity in 2D. The reliance of these "secondary" parameters to inotropy in the 2D systems was not automatically intuitive and may be a quirk of hiPSC-CMs, hence require adaptations in interpreting the data from this model system. Of the platform-cell configurations, responses in EHTs aligned most closely to the free therapeutic plasma concentration. This study adds to the notion that hiPSC-CMs could add value to drug safety evaluation.

Diagnóstico de la situación de salud Departamento Vargas. Distrito Federal, 1984 y análisis técnico-administrativo de la Unidad Sanitaria de La Guaira 1984 / Status health diagnostic, Vargas Department, Federal District, 1984, and technical-administrativ analisys of Unidad Sanitaria de la Guaira, 1984

Siguiendo un orden de ideas basadas en conceptos referentes a los componentes del nivel de vida, tales como indicadores indirectos de salud, e indicadores directos (natalidad, mortalidad), los autores de este trabajo hicieron un estudio descriptivo del Departamento Vargas, el diagnóstico de salud de la comunidad y un análisis técnico-administrativo de la Unidad Sanitaria de la Guaira. Se aplicaron entrevistas lo cual reflejó una situación grave en relación a las causas de morbilidad que indican una mezcla de patologías que tienen que ver con condiciones precarias de saneamiento ambiental, deficiencia de educación sanitaria, bajo nivel de instrucción y bajos ingresos. La investigación sanitaria arrojó bajo rendimiento en la prestación de servicios médicos, por lo que se recomienda establecer un sistema de dapartamentalización que facilite la atención médica y la evaluación técnico-administrativa